Systemic carnitine deficiency is a highly fatal disease affecting children and young adults. The exact etiology of the disease is not understood. Three hypotheses will be tested: (a) Systemic carnitine deficiency results from a defeat in carnitine biosynthesis; (b) the disease is caused by excessive renal excretion of carnitine; and (c) carnitine deficiency is caused by abnormal degradation of carnitine. Using experimental animals, techniques will be developed for measuring lysine methylation (the first step in carnitine biosynthesis) in tissues and quantitation of the reaction product, epsilon-N-trimethyl-L-lysine, in serum and urine. A possible inhibitor and/or repressor of carnitine biosynthesis, beta-chloro-gamma-N-trimethylaminobutyrate, will be synthesized and used to study regulation of the carnitine biosynthetic pathway, and possibly provide an animal model for systemic carnitine deficiency. Carnitine biosynthesis and degradation in patients with systemic carnitine deficiency and normal volunteers will be assessed by intravenous injection of (methyl-3H) epsilon-N-trimethyl-L-lysine, a carnitine precurosr. Carnitine and other metabolites of this compound will be quantitated in serum and urine for 48 hours. Activity of the individual enzymes of the pathway of carnitine biosynthesis will be measured in biopsy and autopsy liver specimens from patients with this disease. Renal excretion of carnitine will be assessed by measuring fractional excretion and tubular maximum reabsorption of carnitine in patients and normal volunteers. These studies will improve our knowledge of carnitine biosynthesis, metabolism and excretion in mammalian systems and provide a better understanding of the etiology of systemic carnitine deficiency. It should also lead to better treatment of the disease.